Therapeutic quinoline compounds



United States Patent 9 THERAPEUTIC oumorma COMPOUNDS Charles'F. Gescllickter, Keusington, Md., and Leonard M. Rice, Falls Chufh, Va.

N Drawing. Application December 9, 1954,

Serial N0. 474,287

11 Claims. (Cl. 260-2412 This inveutionrelates to compositions of matter, particularly to chemotherapeutic, organic compounds and methods of their preparation, and more particularly to compounds characterizedby physiological activity as antihistamines and bronchial dilators and useful in the treatment of respiratory disorders, certain types of abnormal cardiovascular conditions, and for the relief of arthritis.

Specifically the invention involves the discovery and contemplates the disclosure of novelcompounds derived from quinoline and includes the bases themselves and the simple salts thereof.

Accordingly, it is a basic object of the present inventionto provide novel organic compounds and methods for the preparation thereof.

Another objectis to provide novel physiologically active compounds characterized by chemotherapeutic or medicinal properties in the treatment of certain diseases including respiratory disorders, arthritis and cardiovascular disorders and particularly characterized by antihistaminic and bronchiodilatory activity.

A more specific object is to provide novel compounds, namely, Mannich derivatives of 4-carboethoxy-6-hydroxy quinoline.

Another important object of the-invention is the provision of methodsof synthesizing the novel compounds referred to in the foregoing objects. These and subordinate objects and the manner in which they are accomplished will become apparent to those conversant with the art from the following description of the general class of compounds and certainspecific examples of particular members thereof as well as general and Specific methods of their synthesis.

The novel chemotherapeutic compounds discovered are 4-carb0ethoXy-6-hydroxy substituted quinolines having dialkylamino methyl or heterocyclic substituted methyl Mannich groups in the number 5 position of the quinoline nucleus as shown by the following general structural formulae:

I COOCzHs In the above formula, M is (1) a Mannich group of the type /R GHN in which R is an alkyl group having from 1 to 4 carbon atoms or (2) a Mannich group of the type in which the portion 2,803,627 Patented Aug. 20, 1957 .2 represents .a heterocyclic ring such as piperidine, morpholine, pyrrolidine and N-methylpiperazine. Hereinafter, the symbol N R will be used generically to represent and indicate both the dialkyl and heterocyclic portions of the various Mannich groups which, therefore, would be represented by the type formula Still referring to the above formula,.it will be noted that the Mannich group M is shown in the'number 5 position, attached by a bond indicated by a solid line and in the 7 position attached by a bond indicated by a broken or dotted line. This expedient is resorted to in order to show the possible alternative sites of the Mannich group which has not, as yet, been positively ascertained. It is believed that the Mannich group attaches at the number 5 position and therefore, for the remainder of the description and for the purposes of the'subjoined claims it will be presumed that this is the case. It will be understood, however, that there is a recognized possibility that the Mannich group bonds at the 7 position and that the present invention isin-no way limited to or predicated solely on the location of the group at the number 5 position.

Salt formation occurs on both the nitrogens, i. e., on the nitrogen of the quinoline nucleus and the nitrogen of the Mannichgroupas shown in the following formula where HX represents asi'mple salt, for example, a hydrochloride.

In general, the novel products embraced by the invention may be prepared by reacting 4-carboethoxy-6-hydroxy 4-carb0ethoxy-S-morpholinamethyl-o-hydrovcy quinoline (hydrochloride) With the aid of gentle heating, 4.3 grams of 4-carboethoxy-o-hydroxy quinoline was dissolved in 200 ml. of alcohol. To the resulting solution was added 1.7 grams of a 40% aqueous solution of formaldehyde followed by 2 grams of moipholine. The resulting mixture, red in color, Was refluxed for about 8 hours and then allowed to cool. After cooling, the mixture was evaporated to dryness under vacuum and the resulting powder scraped out. The powder was dissolved in absolute alcohol and, the resulting solution treated with decolorizing charcoal, boiled and filtered. The filtrate was acidified by the addition of an excess of alcoholic hydrogen chloride. At this stage the solution was clear yellow.

Ether was added to the cold solution until crystallization started. After several hours of refrigeration, the crystallized product was filtered olf, washed with ether and dried. The product was then recrystallized several times from alcohol to which a few drops of alcoholic hydrogen chloride had been added. Ether was used to induce crystallization. The final product was light yellow in color, melted at 153-155 C. and had the following theoretical and actual analysis:

Actual Theoretical Content Cal- Content culated for Formula O17H22N204C1LH20 Carbon, Percent- 50. 3 50. 13 Hydrogen, Percent. 5. 94 5. 94 Nitrogen, Percent 7. l8 6. 88 Chlorine, Percent" 17.44 17. 41 Oxygen, Percent 20. O 19. 64

EXAMPLE II 4-carb0ethoxy-5-diethylamin0methyl-d-hydroxy quinoline (hydrochloride) Actual Theoretical Content Cal- Content cula d for Formula O11H24N203C12.Hz0

Carbon, Percent. 52. 51. 91 Hydrogen, Percent. 6. 60 6. 66 Nitrogen, Percent 6.94 7. 12 Chlorine, Percent 17. 83 18.03 Oxygen, Percent 16. 60 16. 27

EXAMPLE III 4-carboethoxy-5-piperidylmethyl-6-hydr0xy quinoline (hydrochloride) To 8.6 grams of 4-carboethoxy-6-hydroxy quinoline, dissolved in 250 ml. of warm alcohol, was added 4 grams of a 40% aqueous solution of formaldehyde and 4 grams of piperidine dissolved in 10 ml. of alcohol. The mixture was refluxed for about 10 hours and then allowed to cool. The alcohol and excess of reactants were removed from a water bath with the aid of vacuum. The resulting solid was then dissolved in absolute alcohol, treated with decolorizing charcoal and filtered. When cold, the filtrate was treated with an excess of an alcoholic solution of hydrogen chloride. Ether was added to produce a turbid solution which, after refrigeration, yielded crystals.

The crystalline product was filtered off and Washed with an alcohol-ether mixture and finally with dry ether. Upon recrystallization from alcohol-ether, the product separated in the form of almost colorless crystals which, after being filtered off, dried, washed with ether and dried again, melted at 159-162 C. and yielded the following analytical data:

Theoretical Content Actual Oxygen, Percent 4 EXAMPLE 1v 5 N -m'ethyl piperazine N 'methyl -6-hydr0xy-4- carboethoxy quinoline trihydrochloride With the aid of gentle heating, 20 grams of 6 hydroxy- 4-.carboethoxy quinoline was dissolved in 200 ml. of

alcohol. To the resulting solution was added 15 grams of a 37% aqueous solution of formaldehyde followed by 11 grams of N-methyl piperazine. The resulting mixture, red in color, was refluxed for about 8 hours and then allowed to cool. After cooling, the mixture was evaporated to dryness under vacuum and the resulting powder scraped out. The powder was dissolved in absolute alcohol and the resulting solution treated with decolorizing charcoal, boiled and filtered. The filtrate was acidified by the addition of an excess of alcoholic hydrogen chloride. At this stage the solution was clear yellow.

Ether was added to the cold solution until crystallization started. After several hours of refrigeration, the crystallized product was filtered olf, washed with ether and dried. The product was then recrystallized several times from alcohol to which a few drops of alcoholic hydrogen chloride had been added. Ether was used to induce crystallization. The final product was deep yellow in color, soluble in water, melted at 180 C. and had the following theoretical and actual analysis.

Theoretical Content Calculated for Formula U1s 2uNsOa0 Actual Content As mentioned above, the toxicity of these compounds is very low, the lethal dose for the morpholine compounds, for example, being 225 mg. per kilogram.

In therapeutic applications, the compounds may be administered by intra-muscular injections, in which case about 12.5 mg. daily has been found to be an elfective average dose or they may be given orally, as in the form of capsules, tablets or the like in which case the dosage is raised to about 50 mg. daily.

From the foregoing description of a novel class of compounds, particular exemplary members of the class and methods of synthesizing same, it will be understood that, On the basis of the discovery and intelligence disclosed herein, other specific compounds can be made and variations in the methods of synthesis resorted to. Therefore, the specific compounds and methods disclosed herein are to be considered in all respects illustrative and not restrictive, the scope of the discovery being indicated by the appended claims rather than the foregoing description and all specific compounds and variations in method Which come within the meaning and range of equivalency of the claims are intended to be embraced therein.

This is a continuation-in-part of our application Serial No. 434,674, filed June 4, 1954.

What is claimed and desired to be secured by United States Letters Patent is:

1. A compound selected from the group consisting of (1) compounds having the formula:

R (5 C O O O H wherein R is a radical selected from the group consisting of dimethylamine, diethylamine, dipropylamine, dibutylamine, morpholine, piperidine, pyrolidine and N-methylpiperazine and (2) the acid addition salts thereof.

2. An acid addition salt of S-(N-methyl piperazine N-methyl)-6-hydroxy-4-carboethoxy quinoline.

3. An acid addition salt of 4-carboethoxy-S-morpholinomethyl-6-hydroxy quinoline.

4. An acid addition salt of 4-carb0ethoxy-5-piperidy1 methyl-6-hydroxy quinoline.

5. An acid addition salt of 4-.carboethoxy-5-diethylaminomethyl-6-hydroxy quinoline.

6. An acid addition salt of 4-carboethoxy-5-pyrrolodinylmethyl-6-hydroxy quinoline.

7. The hydrochloride addition salt of 4-carboethoXy-5- morpholinomethyl-6-hydroxy quinoline.

8. The hydrochloride addition salt of 4-carboethoxy-5- diethylaminomethy1-6-hydroxy quinoline.

9. The hydrochlon'de addition salt of 4-carb0eth0xy-5- piperidylmethyI-6-hydroxy quinoline.

References Cited in the file of this patent UNITED STATES PATENTS Woodward July 12, 1949 Burckhalter June 22, 1954 OTHER REFERENCES John ct al., Journal fiir Practische Chemie, vol. 128, pp. 180489, abstracted in Chemical Abstracts, vol. 25, p. 954-(1-2), 1930. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (1) COMPOUNDS HAVING THE FORMULA: 